The present invention relates to a novel type of readily absorbable motilin preparation used to enhance the function of digestive tracts.
Motilin is a peptide hormone present in a digestive tract, which was for the first time isolated from the the mucous membrane of the upper region of the porcine small intestine and structurally determined by J. C. Brown et al. According to ordinary techniques, motilin is now generally extracted from the porcine gastroenteric tract, but its mass production is very difficult. Motilin production by chemical synthesis has also been practiced, but it is again difficult to obtain motilin in large amounts and at low costs on an industrial scale, because motilin contains 22 amino acids.
Applying biotechnology to motilin production is subject to a similar cost-effective problem, because sophisticated steps are needed for obtaining high-purity motilin. With a view to providing a solution to such problems, various motilin-related compounds have recently been synthesized for the stabilization and activity enhancement of motilin, including motilin analogues in which motilin is substituted at the 13-position by leucine or norleucine. We have also discovered and established one industrial way of producing them (see for instance EP-A-0378078A1 filed claiming the priorities of 06.01.89 JP 286/89; 24,08,89 JP216033/89; 24,08,89 JP 216034/89; and 08.11.89 JP 288730/89).
It is also well known that unstable motilins can be stabilized by pH regulation, stabilizers and other means, as set forth in EP-A-437622A1 filed claiming the priorities of 07.07.89 JP 176435/89 and 07.07.89 JP 176436/89. However, this publication provides nothing else than a disclosure of the possible application of known methods for stabilizing polypeptide substances to existing motilins and says nothing about how each substance is used or in what condition it is stabilized.
Motilin is known to have a physiological action on promoting the motility of digestive tracts and contracting the smooth muscles of digestive tracts. Prostaglandins are found to have an action on promoting the motility of digestive tracts as well, but they have a grave defect of having strong side effects. Hitherto, motilins have been expected to be used for promoting the motility of digestive tracts or for treating and diagnosing post-operation gastroenteropathies. Since the motilins are a sort of polypeptides, however, they have production and stability problems. In addition, they are found to be not absorbed in a living system when administrated thereto through administration (e.g., oral or suppository) routes other than injection, and offer a problem as to how their pharmacological action is produced. Thus, the motilins have been considered to be practically inefficacious in the form of pharmaceutics other than injections.
Until now motilins have been administrated to patients by injection, but this has some problems in that injection gives pain to the patients and those who can receive therapy are limited to in-patients.
We have already established an industrial way of producing motilin-like substances which are relatively stable and show strong action (our co-pending U.S. patent application specification) and, now taking this opportunity, we have made an additional investigation of ways for administrating motilins so as to solve the above problems. As a result, we have now found that the use of motilins in combination with specific surface active agents provides an administrating means that is at least equivalent to, or higher than, motilin injections in terms of effect. In other words, we have confirmed that after the oral or nasal administration of motilins combined with surfactants, there can be a remarkable effect on promoting the motility of digestive tracts; that is, the use of motilins combined with surfactants is efficacious for treating the dyskinesia of digestive tracts or contracting the smooth muscles of gastroenteric tracts after surgical operation.
As menitioned above, we have already established a genetic engineering way of producing proteins containing a motilin-like peptide sequence with high purity (see again our co-pending U.S. patent application Serial No. specification).